The proposed studies are designed to examine the interaction of agonists and antagonists with the estrogen receptor and their ability to activate the receptor to the DNA binding state using newly advised equilibrium methods. A new hypothesis for the mechanism of androgen antagonism of estrogen action will be tested both in vitro and in vivo. Additionally, studies of the apparent resistance to steroid hormones observed in New World primates will be carried out. Characterization of plasma and tissue steroid levels as well as binding to transport proteins and receptors will be performed. The possibility that the elevated levels of steroids are the consequence of defects in enzymes that metabolize steroids rather than receptors will be tested by several approaches. This will include comparison of steroid levels in plasma and body fluids such as saliva, studies of steroid metabolism by tissues, and study of steroid dynamics in vivo. The effects of massive aromatization of androgens to estrogens occurring in the male squirrel monkey will be determined. In particular, the influence of the resulting large amounts of estrogens, together with androgens on events such as pubertal development and seasonal weight changes, will be explored. (Y)

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Unknown (R35)
Project #
5R35CA039825-04
Application #
3479115
Study Section
(SRC)
Project Start
1985-07-01
Project End
1992-06-30
Budget Start
1988-07-01
Budget End
1989-06-30
Support Year
4
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Yalcinkaya, T M; Siiteri, P K; Vigne, J L et al. (1993) A mechanism for virilization of female spotted hyenas in utero. Science 260:1929-31
Prins, G S; Cooke, P S; Birch, L et al. (1992) Androgen receptor expression and 5 alpha-reductase activity along the proximal-distal axis of the rat prostatic duct. Endocrinology 130:3066-73
Murai, J T; Mendel, C M; Siiteri, P K (1991) Free fatty acids do not influence the concentrations of free steroid hormones in serum under physiological conditions. J Clin Endocrinol Metab 72:137-9
Papa, V; Hartmann, K K; Rosenthal, S M et al. (1991) Progestins induce down-regulation of insulin-like growth factor-I (IGF-I) receptors in human breast cancer cells: potential autocrine role of IGF-II. Mol Endocrinol 5:709-17
Papa, V; Reese, C C; Brunetti, A et al. (1990) Progestins increase insulin receptor content and insulin stimulation of growth in human breast carcinoma cells. Cancer Res 50:7858-62
Simberg, N H; Murai, J T; Siiteri, P K (1990) In vitro and in vivo binding of toremifene and its metabolites in rat uterus. J Steroid Biochem 36:197-202
Kuhn, R W; VestWeber, C; Siiteri, P K (1988) Purification and properties of squirrel monkey (Saimiri sciureus) corticosteroid binding globulin. Biochemistry 27:2579-86
McCamant, S K; Klosterman, L L; Goldman, E S et al. (1987) Conversion of androgens to estrogens in the male squirrel monkey (Saimiri sciureas). Steroids 50:549-57
Siiteri, P K (1987) Adipose tissue as a source of hormones. Am J Clin Nutr 45:277-82